This randomized phase II trial studies how well trametinib or combination chemotherapy works in treating patients with refractory or advanced biliary or gallbladder cancer or that cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving trametinib is more effective than combination chemotherapy in treating patients with biliary or gallbladder cancer.

Standard abdominal CT scans or MRI from baseline and restaging at 6 weeks will be analyzed using regression equations. These changes will be summarized using descriptive statistics and compared between treatment arms using a two sample t-test or non-parametric Mann-Whitney U test. Potential associations between changes in lean soft tissue and fat mass with changes in levels of interleukin-6 and other cytokines implicated in cancer cachexia will be explored. For each cytokine, the correlation with the Spearman rank correlation coefficient will be estimated.

Standard abdominal CT scans or MRI from baseline and restaging at 6 weeks will be analyzed using regression equations. These changes will be summarized using descriptive statistics and compared between treatment arms using a two sample t-test or non-parametric Mann-Whitney U test. Potential associations between changes in lean soft tissue and fat mass with changes in levels of interleukin-6 and other cytokines implicated in cancer cachexia will be explored. For each cytokine, the correlation with the Spearman rank correlation coefficient will be estimated.

Change in plasma cytokine levels [ Time Frame: Baseline to up to 8 weeks post-randomization ] [ Designated as safety issue: No ]

Pre- and post-treatment levels will be compared within each arm using a paired t-test. The difference in change from baseline at week 4 between treatment arms using a two sample t-test will also be compared. Potential associations between cytokines and clinical outcomes will be assessed using regression models (logistic regression for response, Cox regression for PFS and OS). Odds ratios and hazard ratios for each cytokine variable will be estimated within each arm, and differential effects of the cytokines on clinical outcomes between arms will also be explored.

Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis

Correlative studies

Drug: Trametinib

Given PO

Other Names:

GSK1120212

JTP-74057

MEK Inhibitor GSK1120212

Mekinist

TRAMETINIB

Experimental: Arm IIA (leucovorin calcium, fluorouracil)

Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Fluorouracil

Given IV

Other Names:

5-Fluoro-2,4(1H, 3H)-pyrimidinedione

5-Fluorouracil

5-Fluracil

5-FU

AccuSite

Actino-Hermal

Adrucil

Arumel

Cytosafe

Efudex

Efurix

Fiverocil

Fluoro Uracil

Fluoroplex

FLUOROURACIL

Fluouracil

Flurablastin

Fluracedyl

Fluracil

Fluril

Fluroblastin

Flurox

Ribofluor

Ro 2-9757

Ro-2-9757

Timazin

Other: Laboratory Biomarker Analysis

Correlative studies

Drug: Leucovorin Calcium

Given IV

Other Names:

Adinepar

Calcifolin

Calcium (6S)-Folinate

Calcium Folinate

Calcium Leucovorin

Calfolex

Calinat

Cehafolin

Citofolin

Citrec

Citrovorum Factor

Cromatonbic Folinico

Dalisol

Disintox

Divical

Ecofol

Emovis

Factor, Citrovorum

Flynoken A

Folaren

Folaxin

FOLI-cell

Foliben

Folidan

Folidar

Folinac

Folinate Calcium

folinic acid

Folinic Acid Calcium Salt Pentahydrate

Folinoral

Folinvit

Foliplus

Folix

Imo

Lederfolat

Lederfolin

Leucosar

leucovorin

LEUCOVORIN CALCIUM

Rescufolin

Rescuvolin

Tonofolin

Wellcovorin

Experimental: Arm IIB (capecitabine)

Patients receive capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

I. To determine if a 16-gene expression signature is predictive of mitogen-activated protein kinase kinase (MEK) efficacy as evidenced by improved RR, PFS, and OS.

II. To evaluate the effects of trametinib on the inflammatory cytokine and explore potential associations with response rate and survival.

III. To estimate lean soft tissue and fat mass weight gain as a result of treatment with trametinib vs. capecitabine in patients with advanced refractory biliary cancer.

IV. To bank tissue samples for other future correlative studies including next generation sequencing and whole genome methylation assays. NOTE: These potential future correlative studies will not be performed until an amended protocol with relevant detailed information including specific arms and assays is approved by Cancer Therapy Evaluation Program (CTEP).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive trametinib orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive 1 of 2 treatment regimens at the discretion of the investigator.

ARM IIA: Patients receive leucovorin calcium intravenously (IV) over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM IIB: Patients receive capecitabine PO twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Eligibility

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

DISEASE RELATED CRITERIA

Patients must have histologically or cytologically documented carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or radiologic evidence of unresectable, locally advanced or metastatic disease; patients with ampullary carcinoma are not eligible

Patients must have measurable disease; computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to assess measurable disease must have been completed within 28 days prior to registration; CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)

PRIOR/CONCURRENT THERAPY CRITERIA

Patients must have completed any prior chemotherapy at least 21 days prior to registration and have recovered from any of the effects AND

Patients must have experienced progression to no more than 1 prior regimen of systemic chemotherapy for advanced biliary cancer OR

Patients who received adjuvant chemotherapy and had evidence of disease recurrence within 6 months of completion of the adjuvant treatment are also eligible; if patient received adjuvant treatment and had disease recurrence after 6 months, patients will only be eligible after failing one regimen of systemic chemotherapy used to treat the (unresectable or metastatic) disease recurrence

Patients must not have been treated with prior MEK inhibitors; prior 5-FU or capecitabine treatment is allowed only if given as a radiosensitizer concurrently with radiation therapy at least 12 weeks prior to registration or if given as part of any adjuvant therapy regimen >= 12 months prior to study enrollment

Patients must have no plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy or any other type of therapy (including herbal or natural supplements) for treatment of cancer while on this treatment protocol

For patients who have received prior cryotherapy, radiation therapy, radiofrequency ablation, therasphere, ethanol injection, transarterial chemoembolization (TACE) or photodynamic therapy, the following criteria must be met:

28 days have elapsed since that therapy (lesions that have not been treated with local therapy must be present and measureable)

If the patient has had decompression of the biliary tree within the last 14 days, stability of the bilirubin level needs to be confirmed with two measurements that are within 5 to 7 days of each other; (the second measurement must be obtained within 7 days prior to registration;) both the first and second measurement must be =< 2.0 x IULN; stability is defined as the second measurement being no more than one point higher than the first

Patients must have adequate kidney function as evidenced by at least ONE of the following:

Serum creatinine =< 1.5 x IULN within 28 days prior to registration

Calculated creatinine clearance >= 50 ml/min for patients with creatinine level of 1.0-1.5 x IULN; the serum creatinine value used in the calculation must have been obtained within 28 days prior to registration

Patients with known history or current evidence of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) are not eligible:

History of RVO or RPED, or predisposing factors to RVO or RPED (e.g. such as uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)

Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as:

Evidence of new optic disc cupping

Evidence of new visual field defects

Intraocular pressure > 21 mmHg

NOTE: ophthalmic exam is required for all patients; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration

Patients must have echocardiogram and left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) within 28 days prior to registration; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration

Patients must have an electrocardiogram (ECG) within 28 days prior to registration; patients must have corrected QT interval (QTc) =< 500 msec; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration

Must be able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

Must not have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO) or other agents used in study

Must not have active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible)

Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 4 months after discontinuation of study drug; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years

SPECIMEN SUBMISSION CRITERIA

Patients must submit paraffin-embedded tissue and blood for banking within 28 days after registration; paraffin-embedded tissue from prior surgical resection or from a diagnostic biopsy is acceptable

REGULATORY CRITERIA

Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02042443